Age-related Changes in Auditory Cortex Without Detectable Peripheral Alterations: A Multi-level Study in Sprague-Dawley Rats.

Aging is often considered to affect both the peripheral (i.e. the cochlea) and central (brainstem and thalamus-cortex) auditory systems. We investigated the effects of aging on the cochlea, brainstem and cortex of female Sprague-Dawley rats. The auditory nerve threshold remained stable between the ages of nine and 21 months, as did distortion product otoacoustic emissions and the number of ribbon synapses between inner hair cells and nerve fibers. The first clear signs of aging appeared in the brainstem, in which response amplitude decreased, with thresholds remaining stable until the age of 15 months, and increasing slightly thereafter. The responses of primary auditory cortex neurons revealed specific effects of aging: at 21 months, receptive fields were spectrally narrower and the temporal reliability of responses to communication sounds was lower. However, aging had a null or even positive effect on neuronal responses in the presence of background noise, responses to amplitude-modulated sounds, and responses in gap-detection protocols. Overall, inter-animal variability remained high relative to the variability across groups of different ages, for all parameters tested. Behavioral performance for the modulation depth of amplitude modulation noise was worse in 21-month old animals than in other animals. Age-related alterations of cortical and behavioral responses were thus observed in animals displaying no signs of aging at the peripheral level. These results suggest that intrinsic, central aging effects can affect the perception of acoustic stimuli independently of the effects of aging on peripheral receptors.

Sound Coding in the Auditory Nerve: From Single Fiber Activity to Cochlear Mass Potentials in Gerbils.

Auditory nerve fibers (ANFs) convey acoustic information from the sensory cells to the brainstem using an elaborated neural code based on both spike timing and rate. As the stimulus tone frequency increases, time coding fades and ceases, resulting in high-frequency tone encoding that relies mostly on the spike discharge rate. Here, we recapitulated our recent single-unit data from gerbil's auditory nerve to highlight the most relevant mode of coding (spike timing versus spike rate) in tone-in-noise. We report that high-spontaneous rate (SR) fibers driven by low-frequency tones in noise are able to phase lock ∼30 dB below the level that evoked a significant elevation of the discharge rate, whereas medium- and low-SR fibers switch their preferential mode of coding from rate coding in quiet, to time coding in noise. For high-frequency tone, the low-threshold/high-SR fibers reach their maximum discharge rate in noise and do not respond to tones, whereas medium- and low-SR fibers are still able to respond to tones making them more resistant to background noise. Based on these findings, we first discuss the ecological function of the ANF distribution according to their spontaneous discharge rate. Then, we point out the poor synchronization of the low-SR ANFs, accounting for the discrepancy between ANF number and the amplitude of the compound action potential of the of the auditory nerve. Finally, we proposed a new diagnostic tool to assess low-SR fibers, which does not rely on the onset response of the ANFs.

Loss of function of Ywhah in mice induces deafness and cochlear outer hair cells' degeneration.

In vertebrates, 14-3-3 proteins form a family of seven highly conserved isoforms with chaperone activity, which bind phosphorylated substrates mostly involved in regulatory and checkpoint pathways. 14-3-3 proteins are the most abundant protein in the brain and are abundantly found in the cerebrospinal fluid in neurodegenerative diseases, suggesting a critical role in neuron physiology and death. Here we show that 14-3-3eta-deficient mice displayed auditory impairment accompanied by cochlear hair cells' degeneration. We show that 14-3-3eta is highly expressed in the outer and inner hair cells, spiral ganglion neurons of cochlea and retinal ganglion cells. Screening of YWHAH, the gene encoding the 14-3-3eta isoform, in non-syndromic and syndromic deafness, revealed seven non-synonymous variants never reported before. Among them, two were predicted to be damaging in families with syndromic deafness. In vitro, variants of YWHAH induce mild mitochondrial fragmentation and severe susceptibility to apoptosis, in agreement with a reduced capacity of mutated 14-3-3eta to bind the pro-apoptotic Bad protein. This study demonstrates that YWHAH variants can have a substantial effect on 14-3-3eta function and that 14-3-3eta could be a critical factor in the survival of outer hair cells.

Validation of the French-language version of the OTOSPEECH automated scoring software package for speech audiometry.

OBJECTIVES: To validate a novel speech audiometry method using customized self-voice recorded word lists with automated scoring. PATIENTS AND METHODS: The self-voice effect was investigated by comparing results with prerecorded or self-recorded CVC (consonant-vowel-consonant) word lists. Then customized lists of 3-phoneme words were drawn up using the OTOSPEECH software package, and their scores were compared to those for reference lists. Finally, the customized list scores were compared on automated (Dynamic Time Warping [DTW]) versus manual scoring. RESULTS: Self-voice did not change scores for perception of CVC words at 10, 20 and 30 dB (ANOVA>0.05). Scores obtained with pre-recorded and self-recorded lists correlated (n=10, R(2)=0.76, P<0.01). Customized list scores correlated strongly with the reference cochlear lists of Lafon in normal-hearing (n=77, R(2)=0.83, P<0.001) and hearing-impaired populations (n=13, R(2)=0.89, P<0.001). Results on the automated and manual scoring methods correlated in both populations (n=77, R(2)=0.71, P<0.01; and n=13, R(2)=0.76, P<0.01, respectively), with DTW scores ranging from 24.17 to 53.24. CONCLUSIONS: Automated scoring of customized self-voice recorded lists for speech audiometry displayed results similar to conventional audiometric techniques.

Prevention of trauma-induced cochlear fibrosis using intracochlear application of anti-inflammatory and antiproliferative drugs.

Cochlear fibrosis is a common finding following cochlear implantation. Evidence suggests that cochlear fibrosis could be triggered by inflammation and epithelial-to-mesenchymal cell transition (EMT). In this study, we investigate the mechanisms of cochlear fibrosis and the risk/benefit ratio of local administration of the anti-inflammatory drug dexamethasone (DEX) and antimitotic drug aracytine (Ara-C). Cochlear fibrosis was evaluated in cochlear fibrosis models of rat cochlear slices in vitro and in KLH-induced immune labyrinthitis and platinum wire cochlear implantation-induced fibrosis in vivo. Cochleae were invaded with tissue containing fibroblastic cells expressing α-SMA (alpha smooth muscle actin), which along with collagen I, fibronectin, and laminin in the extracellular matrix, suggests the involvement of a fibrotic process triggered by EMT in vitro and in vivo. After perilymphatic injection of an adenoviral vector expressing GFP in vivo, we demonstrated that the fibroblastic cells derived from the mesothelial cells of the scalae tympani and vestibuli. Activation of inflammatory and EMT pathways was further assessed by ELISA analysis of the expression of IL-1ß and TGF-ß1. Both markers were elevated in vitro and in vivo, and DEX and Ara-C were able to reduce IL-1ß and TGF-ß1 production. After 5days of culture in vitro, quantification of calcein-positive cells revealed that Ara-C was 30-fold more efficient in preventing fibrosis, and provoked less sensory hair cell loss, than DEX. In KLH-induced immune labyrinthitis and platinum wire-implanted models, Ara-C was more efficient in preventing proliferation of fibrosis with less side effects on hair cells and neurons than DEX. In conclusion, DEX and Ara-C both prevent fibrosis in the cochlea. Analysis of the risk/benefit ratio favors the use of Ara-C for preventing cochlear fibrosis.

Plaque rupture and morphological characteristics of the culprit lesion in acute coronary syndromes without significant angiographic lesion: analysis by intravascular ultrasound.

PURPOSE: To evaluate by intravascular ultrasound (IVUS) the characteristics of the culprit lesion with plaque rupture without significant angiographic stenosis after acute coronary syndromes (ACS). PATIENTS AND METHODS: After ACS, IVUS was performed in 68 patients (46.8 years±11.9) without significant angiographic stenosis (31±15%). Plaque rupture was defined as a cavity within the plaque, communicating with the arterial lumen and having an overlying residual fibrous cap fragment. Qualitative analysis defined the type of plaque, and quantitative analysis evaluated plaque plus media area, plaque volume, plaque burden, and arterial remodeling index. Patients were divided into two groups: Group I with plaque rupture (25 patients) and Group II without plaque rupture (43 patients). RESULTS: All patients with rupture showed soft or mixed plaque but no calcified plaque. In Group I, plaque rupture was associated with a larger plaque burden (49.8±12.3% vs. 39.8±12.1%, P<.0005), a more significant plaque plus media area (7.44±2.9 vs. 5.24±2.4mm(2), P<.001), a greater plaque volume (151.9±103.4 vs. 99.2±81.6mm(3), P<.007), and a higher ratio of plaque volume over length (8.0±3.8 vs. 5.6±3.7mm(3)/mm, P<.003). In Group I, positive remodeling was more frequent than intermediate remodeling (P<.03) or negative remodeling (P<.005). In Group II, there was no significant difference between the three types of remodeling. CONCLUSION: The plaque ruptures responsible for ACS frequently appear on voluminous plaques with a large plaque burden and positive arterial remodeling.

A computational model of the primary auditory neuron activity.

Sound translation into neural message at the first auditory synapse is of prime importance for providing organism with sound environment. Here, we compiled experimental features of the primary auditory neurons into a computational model, composed of two distinct compartments (i.e., afferent bouton and axon). Simulation of the model closely reproduces the whole biophysical properties of both excitatory post-synaptic currents and action potentials firing. This simple model provides a powerful tool to understand the synaptic disorders on the sound neural coding at the first auditory synapse.

Predictors of infarct artery patency after prehospital thrombolysis: the multicentre, prospective, observational OPTIMAL study.

OBJECTIVE: To identify predictors of early TIMI 3 flow patency of the infarct-related artery after prehospital thrombolysis in patients with ST-segment elevation myocardial infarction (STEMI) using data from a "real-world" population, and to develop a nomogram for triaging patients to emergency angiography. DESIGN: Multicentre, observational, prospective, cohort study. SETTING: 79 Hospitals in France with a prehospital mobile intensive care unit and a coronary care unit with 24 h access to coronary angiography. PATIENTS: 997 Patients with STEMI. INTERVENTIONS: All patients received prehospital thrombolysis within 6 h of symptom onset and angiography was performed within 6 h of thrombolysis. MAIN OUTCOME MEASURES: Coronary patency (TIMI flow). RESULTS: The median age of the population was 59 years and the sample comprised 18% women. After multivariable logistic regression analysis, predictors of TIMI 3 flow in the infarct-related artery were current/previous smoking (odds ratio (OR) = 1.60, 95% confidence interval 1.15 to 2.22), < or =5 leads with ST-segment elevation before thrombolysis (OR = 1.59, 1.12 to 2.25), Killip class I (OR = 1.96, 1.05 to 3.67), chest pain relief (OR = 1.62, 1.17 to 2.25) and ST-segment resolution > or =70% (OR = 1.76, 1.29 to 2.38). A nomogram was developed to assess the probability of TIMI 3 flow, according to smoking status, number of leads with ST elevation before thrombolysis, Killip class, chest pain relief and ST-segment resolution. CONCLUSIONS: This study provides quantitative data for predicting success of prehospital thrombolysis. The nomogram is a simple tool for predicting likelihood of coronary patency, based on clinical and electrocardiographic data. It may help to identify patients who require emergency angiography and rescue percutaneous coronary intervention.

Clinical and angiographic results of angioplasty with a paclitaxel-eluting stent for unprotected left main coronary artery disease (a study of 101 consecutive patients).

BACKGROUND: After coronary stenting with drug eluting stents, long-term clinical outcome of unprotected left main coronary artery disease is unknown, even large scale registries or randomised trials with coronary artery bypass graft are ongoing. AIMS: To report clinical and angiographic results of paclitaxel-eluting stent implantation for left main coronary artery stenosis (a series of 101 consecutive patients). METHODS: This report is a prospective study performed to evaluate the immediate and mid-term clinical and angiographic outcomes of patients undergoing paclitaxel-eluting stent (PES) implantation for unprotected left main coronary artery (LMCA) stenosis. From January 2004 to December 2005, 101 consecutive patients were stented with paclitaxel-eluting stents (the provisional T stenting technique followed by Kissing balloon for distal left main vessel disease). RESULTS: Mean age was 68.9+/-11.07 years. 73.3% of patients were male. Acute coronary syndrome was present in 65% of patients, of whom 22.8% had ST elevation. Distal left main trunk lesions were present in 87.1% of cases. Three-vessel disease represented 7% of cases. Angiographic success was obtained in 97.03% of patients with an acute gain of 2.18+/-0.53mm. GpIIbIIIa inhibitors were used in only 8.9% of cases. Hospital stay was 7.6 +/- 3.7 days. In-hospital complications were present in 7.9%, with a hospital mortality rate of 2%. At six month follow-up, the rate of target lesion revascularization (TLR) was 3%, and the rate for major adverse cardiac events (MACE) was 8.9%. Angiographic control was performed in 88.1% and a late loss of 0.1mm (0.04-0.2mm) was noted. Re-stenosis occurred in 4 patients (4.5% of cases). 4 patients (4%) died, including 2 from cardiac causes. CONCLUSION: Paclitaxel-eluting stent implantation for unprotected left main coronary disease appears to be safe with high procedural success rate and a low re-stenosis rate at six month-follow-up.

Long-term clinical outcome after percutaneous coronary interventions in the elderly: results for 512 consecutive patients.

AIMS: Elderly patients are increasingly being referred for percutaneous coronary intervention (PCI), but there is a paucity of current data on the long-term outcome of elective PCI in elderly patients. We sought to define the risks facing elderly patients undergoing contemporary PCIs. METHODS AND RESULTS: Retrospectively, in a single-centre registry, we studied the mortality and the outcome of 512 consecutive patients > 75 years old who underwent PCI, between January 1st 2000 and December 31st 2001. Clinical endpoints included in-hospital mortality; major adverse cardiovascular and cerebro-vascular events (MACCE) defined by the components of death, myocardial infarction, stroke, and repeat coronary revascularisation (target vessel revascularisation or not) by surgery or PCI, within the hospitalisation period and at long-term follow up. We compared 315 patients 75-79 years old (group I) with 197 patients > 80 years old (group II). In-hospital mortality and MACCE rates were not different between the two groups. Independent predictors of in-hospital major events found by multivariate analysis were: ST-segment elevation myocardial infarction or STEMI (Odds Ratio [OR]=2.58, 95% CI=1.15-5.78), left ventricular ejection fraction or LVEF <40% (OR=4.98, 95% CI=2.19-11.36) and prior coronary artery bypass grafting or CABG (OR=3.13, 95% CI=1.06-9.26). Mean long-term follow-up was 51.3 months. Death was significantly more frequent in the older group (42% vs 26%, p<0.0001). Independent predictors of long-term mortality found by multivariate analysis were: LVEF < 40% (Hazard Ratio=4.12, 95% CI=2.69-6.32), creatinine rate (HR=1.00, 95% CI=1.00-1.006) use cut-off see table and prior carotid surgery or stroke (HR=2.2, 95% CI=1.19-4.14). CONCLUSIONS: Although age is not an independent predictive factor of morbidity or mortality, co-morbidities in the elderly strongly influence long-term clinical outcomes after PCI.

Comparison of three spike detectors dedicated to single unit action potentials of the auditory nerve.

This paper compares three methods for the detection of single unit action potentials in auditory nerve. The detector structures are similar consisting of a filtering procedure in the first stage and a decision rule in the second stage. The detection accuracy of each detector is characterized by the couple probability of a true detection vs. rates of false detection with synthetic data. The performance comparison between detectors shows that the detector using a band-pass finite-impulse-response filter with complex coefficients offers the best performance. This observation was especially evident for low signal to noise ratios. This finding is confirmed with real data and leads us to revise the protocol of spike detection in auditory nerve.

Differential expression of PKC beta II in the rat organ of Corti.

To investigate a possible involvement of protein kinase C (PKC) in cochlear efferent neurotransmission, we studied the expression of the calcium-dependent PKC beta II isoform in the rat organ of Corti at different postnatal ages using immunofluorescence and immunoelectron microscopy. We found evidence of PKC beta II as early as postnatal day (PND) 5 in efferent axons running in the inner spiral bundle and in Hensen cells. At PND 8, we also found PKC beta II in efferents targeting outer hair cells (OHCs), and a slight detection at the synaptic pole in the first row of the basal and middle cochlear turns. At PND 12, PKC beta II expression declined in the efferent fibres contacting OHCs, whereas expression was concentrated at the postsynaptic membrane, from the basal and middle turns. The adult-like pattern of PKC beta II distribution was observed at PND 20. Throughout the cochlea, we found PKC beta II expression in the Hensen cells, non-sensory cells involved in potassium re-cycling, and lateral efferent terminals of the inner spiral bundle. In addition, we observed expression in OHCs at the postsynaptic membrane facing the endings of the medial efferent system, with the exception of some OHCs located in the most apical region of the cochlea. These data therefore suggest an involvement of PKC beta II in both cochlear efferent neurotransmission and ion homeostasis. Among other functions, PKC beta II could play a role in the efferent control of OHC activity.

Differential display fingerprints: new approach to characterize smooth muscle cells and human coronary atherectomy tissues.

AIM OF THE STUDY: Smooth muscle cells build up the normal media and stabilize atherosclerotic lesions whereas an inflammatory component is determinant for unstable angina. Smooth muscle cells, currently identified by alpha-actin, present a phenotypic heterogeneity and alpha-actin can be reduced in pathology. We tried to characterize vascular cell types, particularly smooth muscle cells, and coronary atherosclerotic tissues, by random genes expression fingerprints. MATERIALS AND METHODS: Expression fingerprints (cDNA electrophoresis) were performed by differential display reverse transcriptase-polymerase chain reaction. Variability of fingerprints was studied for a panel of arterial muscle cell phenotypes and comparisons were made with fingerprints from other cell types (endothelial cells and macrophages). The technique was then applied to human coronary atherectomy samples compared to control human arterial (mammary) smooth muscle. RESULTS: Arterial smooth muscle cells fingerprints were overall similar whatever the cell phenotype (native contractile, dedifferentiated in culture or epithelioid). Moreover, with two primer pairs, the muscular fingerprints markedly differed from the endothelial and the monocytic fingerprints. Application of differential display to coronary atherectomy samples was feasible. Interestingly, the pathological tissues exhibited either smooth muscle-like or smooth muscle-divergent fingerprints. CONCLUSIONS: Smooth muscle cells and inflammatory cells exhibited distinct differential display fingerprint patterns. Thus, a simple expression profile of arbitrary genes provides a molecular bar code tool (pattern signature) useful to characterize vascular cell cultures or tissues. The present work proposes a method to analyze coronary atherectomy samples which estimates their whole quality, muscular versus non muscular (inflammatory), this is of interest for clinical research.

Coxsackie adenovirus receptor and alpha nu beta3/alpha nu beta5 integrins in adenovirus gene transfer of rat cochlea.

This study was designed to determine whether Coxsackie adenovirus receptor (CAR) and alpha nu beta3/alpha nu beta5 integrin co-receptors are involved in adenovirus gene transfer in the rat cochlea. We find that CAR and integrin co-receptors are expressed in every cell subtype transduced by the adenoviral vector Ad5 DeltaE1-E3/cytomegalovirus/green fluorescent protein (GFP) on cochlear slices in vitro. The spiral ganglion neurons, which do not express CAR, were not transduced by the virus. Blocking these receptors by monoclonal antibodies decreased transgene expression, whereas disrupting tight junctions with ethylenediaminetetraacetic acid led to an increased transgene expression. However, sensory hair cells and strial cells also expressing CAR and alpha nu integrins were not transduced by the vector. GFP expression was also studied in vivo. Perilymphatic perfusion of adenovirus in vivo did not affect hearing and only cells lining the perilymphatic spaces were transduced. Endolymphatic perfusion resulted in low-frequency hearing loss and although some cells of the organ of Corti were efficiently transduced, the sensory and the strial cells were not. Transduced sensory and strial cells were occasionally observed in cochleas after single shot of adenovirus. Pretreatment with anti-CAR and anti-alpha nu antibodies decreases GFP expression in vivo, suggesting that the CAR/alpha nu integrin pathway is involved in adenovirus transduction in the cochlea.

Evaluation of in-stent restenosis in proximal coronary arteries with multidetector computed tomography (MDCT).

The purpose of this study was to assess the ability of 16-slice computed tomography (CT) to detect in-stent restenosis of proximal coronary arteries. From November 2002 to April 2004, 134 consecutive patients with proximal stents (3.25 +/- 0.47 mm) were prospectively studied. Multidetector CT (MDCT) was performed 24 h (baseline) and 6 months after angioplasty and analysed by two radiologists blinded to the results of the coronary angiography. Sensitivity, specificity, positive and negative predictive values for in-stent restenosis were compared with conventional quantitative coronary angiography (QCA). Stenosis with a diameter >or=50% was considered diagnostic of in-stent restenosis. The CT analysis was performed in 131 and 114 patients at baseline and 6 months, respectively. The in-stent lumen was evaluable in 111 (121 stents) and 99 patients (108 stents) at baseline and 6 months, respectively. The prevalence of in-stent restenosis was 22.5%. Restenoses were correctly identified in 91.7 and 87.5% by the two radiologists. The sensitivity, specificity, positive and negative predictive values for the assessment of significant in-stent restenosis were 92, 67, 43, 97% and 87, 66, 41, 95% for the radiologists, respectively. MDCT is a potential non-invasive technique for the screening of in-stent restenosis of proximal coronary arteries that needs further improvements.

Cochlear NMDA receptor blockade prevents salicylate-induced tinnitus.

Large doses of aspirin produce reversible hearing loss and tinnitus. These effects have been attributed to the salicylate ion, the active component of aspirin. Salicylate acts as a competitive antagonist at the anion-binding site of prestin, the motor protein of sensory outer hair cells. This provides an explanation for the hearing loss induced by aspirin. However, the molecular mechanism of salicylate-induced tinnitus remains obscure. One physiological explanation is that salicylate ototoxicity is likely to originate in an alteration to arachidonic acid metabolism. Arachidonic acid potentiates NMDA receptor currents. We therefore tested the involvement of cochlear NMDA receptors in the occurrence of tinnitus. Tinnitus was assessed with a behavioural test based on an active avoidance paradigm. Results showed that the tinnitus induced by salicylate may be suppressed by the introduction of NMDA antagonists into the cochlear fluids. To determine if the activation of NMDA receptors was linked to cyclooxygenase inhibition, we investigated the effect of mefenamate (a potent cyclooxygenase inhibitor). Since NMDA antagonists also blocked mefenamate-induced tinnitus, we suggest that salicylate-induced tinnitus is mediated by cochlear NMDA receptors through the inhibition of cyclooxygenase activity. Target cochlear NMDA receptors may therefore present a therapeutic strategy for the treatment of tinnitus.

Are there good and bad responders to prehospital thrombolysis in the acute phase of myocardial infarction? OPTIMAL study rationale.

The effectiveness of thrombolytics has been clearly demonstrated in more than half the cases in the large cohorts of patients selected for trials during the acute phase of myocardial infarction. At individual level, thrombolysis will clinically either succeed or fail so, for the medical team managing the patient, choice of treatment may be likened to a gamble which in the best of cases (most often) leads to an uncomplicated success and, in the worst of cases, failure worsened by a severe complication. OPTIMAL is a multidisciplinary and multicentre, prospective cohort study associating mobile medical teams and interventional cardiology units to test the hypothesis that the outcome of prehospital thrombolysis does not depend on chance alone but also varies according to demographic, etiological, clinical and logistic factors involved in the occurrence and management of myocardial infarction. The primary objective of this French study, conducted over one year on more than 800 subjects, is to identify the predictors of the results of prehospital thrombolysis from a very early angiographic evaluation. The results for this cohort may be useful for setting up appropriate management strategies for acute myocardial infarction, from the prehospital phase (thrombolysis or not) up to in-hospital orientation of the patients (angiography room or Intensive Care Unit) and to determine the most judicious time for coronary angiography. OPTIMAL is to date the largest prospective serie of prehospital thrombolysis evaluated by an early angiographic control.

[Percutaneous closure of three septal defects by two Amplatz occluders implanted during the same procedure]. / Fermeture percutanée de 3 communications interauriculaires par 2 dispositifs d'Amplatz implantés au cours d'un même cathétérisme.

Multiple atrial septal defects can be closed by interventional catheterisation. The procedure requires an accurate morphological evaluation: number of defects, distance from their edges to the main cardiac structures, resistance of the septum. The authors report the case of a 63 year old woman presenting with cardiac failure in whom 3 atrial septal defects were diagnosed. All 3 defects were successfully closed by the implantation of two Amplatz devices. Control echocardiography at 6 months showed the occluders in a normal position with no residual shunt and the patient was asymptomatic.